Composition for treating or preventing liver cancer.

A composition and technology for hepatocellular carcinoma, which are applied in the directions of drug combinations, active ingredients of heterocyclic compounds, and medical preparations containing active ingredients, etc., to achieve the effects of inhibiting tumor proliferation, reducing TERT expression, and reducing telomere length.

Active Publication Date: 2018-12-21
SHUOSHI MEDICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, nothing is known about the role of idelalis in liver cancer, especially advanced hepatocellular carcinoma, and the development of therapeutic agents for advanced hepatocellular carcinoma is needed

Method used

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  • Composition for treating or preventing liver cancer.
  • Composition for treating or preventing liver cancer.
  • Composition for treating or preventing liver cancer.

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Example 1. Determination of inhibition of HCC cell proliferation, TERT expression, and maintenance of telomere length by adelaris as a PI3K-Akt inhibitor

[0090] Due to the activity of blocking PI3K-AKT signal transduction, adelaris as a selective p110δ kinase inhibitor has been used to treat patients with chronic lymphocytic leukemia (Yang Q et al., "Clinical Cancer Research" (Clin. CancerRes) 2015; 21:1537-42; Fruman DA et al., "Nat Rev Drug Discov" (Nat Rev Drug Discov) 2014; 13:140-56). In order to measure the activity of adelaris in hepatocytes in which p110δ is latently present at different levels, the inventors of the present invention conducted a proliferation test by using three hepatic cell lines. These liver cell lines include Huh7 cells and Hep3B cells, which come from patients with early HCC and show high levels of p110δ ( figure 1 A and B), which also includes the THLE-3 cell line, which is an immortalized human liver epithelial cell line derived from normal...

Embodiment 2

[0093] Example 2. Determination of the inhibition of ROS-induced TERT up-regulation and telomere extension by adelaris in HCC cells

[0094] It has been previously confirmed that ROS can over-activate the PI3K-AKT signal transduction pathway in cancer cells (Brazil DP et al. "Cell" (Cell), 2002; 111:293-303; Li VS et al. "Cell" (Cell) 2012; 149:1245-56). However, it is not clear whether PI3K isoforms are increased by ROS to induce PI3K-AKT activation. Because the expression of PI3K isoform p110δ in HCC cells is higher than that in THLE-3 cells ( figure 1 with figure 2 A), and adelaris as a selective inhibitor of p110δ can only inhibit pAKT and TERT expression and telomere maintenance in HCC cells, so the inventors of the present invention conducted experiments to observe the expression of p110δ in HCC cells Whether it is increased by ROS. In the class I PI3K isoforms (p110α, p110β, p110δ and p110γ), hydrogen peroxide (H 2 O 2 ) After being treated as a ROS inducer, only p110δ ...

Embodiment 3

[0097] Example 3. Determination of the in vivo inhibition of Idelalix as a PI3K inhibitor on ROS activity related to HCC tumor growth promotion

[0098] The inventors of the present invention conducted research to observe whether the increase in chromatin accessibility in the TERT promoter during TERT transcription is related to β-catenin. To this end, chromatin immunoprecipitation was performed by using endogenous β-catenin and an antibody against histone methyltransferase SetD1A (which has been reported to promote TERT transcription based on chromatin remodeling). When PI3K or AKT inhibitors are treated together for chromatin immunoprecipitation, even in the presence of H 2 O 2 In the case of, β-catenin and SetD1A (which bind to the TERT promoter in HCC cells) are also reduced ( image 3 A and 3B). However, when GSK3β inhibitors are also used for treatment, whether H 2 O 2 Treated or not, both showed increased binding of β-catenin and SetD1A ( image 3 C). These results indica...

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PUM

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Abstract

The present application relates to a pharmaceutical composition containing compound 5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4-3H)-quinazolinone, and a pharmaceutically acceptable saltthereof for preventing and treating liver cancer, and the composition of the present application inhibits ROS-PI3K-AKT-TERT signal transduction, and thus can be favorably used in the treatment of a liver cell cancer, in which a protein involved in the signal transduction is overexpressed, especially, advanced liver cell cancer.

Description

Technical field [0001] The present invention relates to a composition for the prevention and treatment of liver cancer. Background technique [0002] Liver cancer is the second leading cause of cancer deaths worldwide, and hepatocellular carcinoma (HCC) accounts for 85% to 90% of liver cancers. Almost 70% to 80% of hepatocellular carcinoma is not discovered until it has advanced to an advanced stage. Currently, only Sorafenib as a drug is approved as a specific therapeutic agent for advanced hepatocellular carcinoma. [0003] The main cause of HCC is liver cirrhosis. Since liver cirrhosis has many causes such as hepatitis caused by hepatitis virus (ie, HBV or HCV), alcohol consumption, or non-alcoholic fatty liver, it is difficult to formulate a strategic plan for the treatment of HCC patients based on the personal medical history of liver cirrhosis. [0004] It is known that multiple pathways including Wnt-β-catenin pathway, p53-Rb pathway, chromatin remodeling and phosphatidylin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/52A61K31/517A61K9/16A61K9/20A61K9/48
CPCA61K31/52A61P35/00A61K9/16A61K9/20A61K9/48A61K31/517
Inventor 郑求兴金允骏高恩京
Owner SHUOSHI MEDICAL CO LTD
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